Highlights from Recent Cancer Literature
Journal: Cancer Research (2019)

The poor survival of patients with metastatic colorectal cancer highlights the tremendous clinical need for effective therapy. Van den Eynde and colleagues quantified immune cell types and mutational frequency in primary and metastatic colorectal cancers to develop an “Immunoscore.” Immune infiltrates were heterogeneous in different metastases within the same patient, as well as across multiple patients. Within any specific patient, high immune infiltrate/high Immunoscore correlated with both fewer metastases and improved survival. Metastases with the lowest Immunoscore in each patient exhibited the strongest association with survival, suggesting that the subset of metastases with the poorest immune microenvironment influences survival. In biopsies of colorectal cancer metastases, the correlation with outcome was better for the Immunoscore than for quantitation of PDL1. Interestingly, anti-EGFR therapy could increase the Immunoscore of colorectal cancer metastases, providing a path to increase the immune microenvironment of colorectal cancer metastases.Expert Commentary: Immune cell infiltration into colorectal cancer metastases may be a predictor of outcome.Van den Eynde M, Mlecnik B, Bindea G, Fredriksen T, Church SE, Lafontaine L, et al. The link between the multiverse of immune microenvironments in metastases and the survival of colorectal cancer patients. Cancer Cell 2018;34:1012–26.D’Angelo and colleagues performed a comprehensive analysis of 35 low-grade (LGG) and 24 high-grade gliomas (HGG) from patients with neurofibromatosis type 1 (NF1). The genetic landscape of NF1-associated glioma revealed alterations similar to those in sporadic HGG, specifically loss of CDKN2A/B, p53 mutations, and ATRX inactivating mutations. However, unlike sporadic gliomas, NF1-associated HGG had gains of TERT rather than TERT promoter mutations. LGGs were characterized by CD8+ immune cell infiltration, consistent with previously generated mouse models of NF1-associated glioma. Finally, array-based DNA methylation analysis of NF1-associated LGGs showed similarities to a previously described cluster of sporadic LGGs, which were pilocytic astrocytoma-like, and suggests that ATRX loss can further refine the classification of this subgroup.Expert Commentary: The finding that NF1-associated low-grade gliomas harbor an immune infiltration signature is consistent with acquired adaptive immunity, which might explain their indolent course. In contrast, NF1-associated high-grade gliomas acquire events similar to sporadic high-grade gliomas, suggesting similar treatment approaches.D'Angelo F, Ceccarelli M, Tala, Garofano L, Zhang J, Frattini V, et al. The molecular landscape of glioma in patients with Neurofibromatosis 1. Nat Med 2019;25:176–87.Arginine is a semiessential amino acid, metabolized by arginase (ARG) 1 and 2, or nitric oxide synthase enzymes. These metabolites provide diverse roles in cell signaling, proliferation, protein synthesis, and immune escape. Fultang and colleagues identify a key shared regulation between tumor cell arginine metabolism and intratumoral macrophages in neuroblastoma. Tumor cells polarize infiltrating monocytes to an M1-macrophage phenotype, which releases IL1β and TNFα in an AKT-dependent manner. IL1β and TNFα establish a feedback loop to upregulate ARG2 expression via p38 and ERK1/2 signaling in neuroblastoma and this process drives tumor cell proliferation.Expert Commentary: Cross-talk between myeloid cells and tumor cells creates a metabolic regulatory loop that enhances neuroblastoma progression. The targeting of both immune and metabolic drivers of tumorigenesis in this study provides a rational and potentially clinically achievable approach in the treatment of neuroblastoma.Fultang L, Gamble LD, Gneo L, Berry AM, Egan SA, De Bie F, et al. Macrophage-derived IL1β and TNFα regulate arginine metabolism in neuroblastoma. Cancer Res 2019;79:611–24.Suppressor of fused (Sufu) negatively regulates Sonic Hedgehog (SHH) signaling by binding to effector GLI transcription factors in the cytoplasm. Alterations of Sufu are common in medulloblastoma (MB). Yin and colleagues report that loss of Sufu will not induce medulloblastoma in mice, because there is not sufficient activation of Gli2. However, loss of both Sufu and speckle-type POZ protein (Spop), an E3 ubiquitin ligase that targets Gli2, led to rapid formation of medulloblastoma. In addition, the transcription factor Atoh1 was identified as an important target of Gli2, which in turn activates the core SHH MB signature genes.Expert Commentary: This study shows the dual role of Sufu in SHH MB and gives mechanistic insights into the transcriptome, which contributes to SHH MB tumorigenesis.Yin WC, Satkunendran T, Mo R, Morrissy S, Zhang X, Huang ES, et al. Dual regulatory functions of SUFU and targetome of GLI2 in SHH subgroup medulloblastoma. Developmental Cell; Published December 7, 2018; doi: 10.1016/j.devcel.2018.11.015.High-grade serous ovarian cancer is characterized by extreme genomic instability. While DNA damaging agents lead to initial responses, virtually all patients relapse. Zeng and colleagues identify the CDK7/12/13 inhibitor, THZ1, as a potent agent in ovarian cancer models, particularly those dependent on MYC expression. From a chemical screen, the authors identified THZ1 as a potent inhibitor of MYC protein abundance and cell growth in patient-derived xenograft models of ovarian cancer, both singly and in combination with olaparib. While treatment with either CDK7 or the CDK12/13 inhibitors produced dose-dependent effects on MYC expression, the combination led to a pronounced decrease in MYC levels. Importantly, downregulation of MYC by THZ1 could be rescued by expression of a THZ1-resistant CDK7 mutation, but was not sufficient to rescue aberrant cancer cell growth, suggesting the contribution of alternate pathways that are affected by THZ1 treatment.Expert Commentary: The study highlights the benefits of targeting multiple transcriptional CDKs simultaneously to prevent or delay resistance due to functional redundancies in transcription regulation.Zeng M, Kwiatkowski NP, Zhang T, Nabet B, Xu M, Liang Y, et al. Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13. Elife; Published November 13, 2018; doi: 10.7554/eLife.39030.Loss-of-function mutations in the tumor suppressor gene RB1 are common in many tumor types. While attempts to target tumor suppressor genes have been challenging, reports from two independent studies (1, 2) using gene-drug and gene-gene screens identified synthetic lethal interactions between RB1 and Aurora kinases. They support a model in which sensitivity of RB1 mutant cells to Aurora kinase inhibition is dependent on the ability of high Aurora kinase activity to override a spindle assembly checkpoint activated in RB1-deficient tumors. Inhibitors of Aurora kinase A and B were effective in RB1-deficient models of small cell lung cancer preclinically.Expert Commentary: These studies identify Aurora kinase inhibition as a potential therapeutic strategy for the treatment of RB1 mutant cancers. The development of inhibitors that are well tolerated in mice is encouraging, and clinical trials are ongoing.1. Gong X, Du J, Parsons SH, Merzoug FF, Webster Y, Iversen PW, et al. Aurora-A kinase inhibition is synthetic lethal with loss of the RB1 tumor suppressor gene. Cancer Discovery; Published First October 29, 2018; doi: 10.1158/2159-8290.CD-18-0469.2. Oser MG, Fonseca R, Chakraborty AA, Brough R, Spektor A, Jennings RB, et al. Cells lacking the RB1 tumor suppressor gene are hyperdependent on aurora B kinase for survival. Cancer Discovery; Published First October 29, 2018; doi: 10.1158/2159-8290.CD-18-0389.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.